Vaccines comprise special preparations of antigenic materials that can be used to stimulate development of antibodies (humoral response) and T cell activity (cellular response), thereby conferring active immunity against a specific disease. Typically, vaccines are produced by culturing bacteria or viruses under conditions that lead to a loss of their virulence, but not of their antigenic nature. Some vaccines consist of specially treated toxins or of dead bacteria that are still antigenic. Live but weakened organisms are also used as vaccines. The immunization of humans or animals with vaccines produces active immunity, i.e., the stimulation of the body to produce its own antibodies.
Because the preparation of new vaccines may prove to be toxic or detrimental to persons immunized with said vaccines, it is desirable to immunize animals with new vaccines in order to determine whether the vaccines are both safe and effective in eliciting humoral antibody response. Although a vaccine may elicit a humoral and cellular response, that immune response may not be effective in protecting the animal from infection. Therefore, to demonstrate the effectiveness of a vaccine, the vaccinated animal should be challenged with the infectious agent. However, this is difficult because the pathogens that the vaccine is designed to protect against may be specific for humans and, therefore, the capacity of the vaccine to protect the animal from infection cannot be determined. Hence, it is desirable to develop an animal system wherein human vaccines may be tested for their abilities to elicit an animal antibody immune response that protects human tissue from infection.
In an unsuccessful attempt to create such animal systems, mice have been implanted with human fetal liver, hematopoietic cells, human fetal thymus and human fetal lymph node. See "The SCID-hu Mouse; Murine Model for the Analysis of Human Hematolymphoid Differentiation and Function", by McCune et al., in Science, Vol. 241, pages 1632-1639 (Sep. 23, 1988), wherein a chimeric mouse was created by implanting human fetal liver hematopoietic cells, fetal thymus and fetal lymph node into SCID mice in an attempt to create a chimeric mouse capable of responding to vaccines with both murine and human cellular immune response and humoral immune response.
The chimeric mouse developed by McCune et al. produced only transient human T cells. The McCune mouse did not produce any murine T cells, and hence the immunodeficient SCID mouse did not have its murine T cell function restored after implantation with human fetal tissue. Moreover, the mouse produced by McCune et al. showed no primary human immune response, and was not capable of any significant human or murine immune response.
Namikawa et al., in "Long-Term Human Hematopoiesis in the SCID-hu Mouse", J. Exp. Med., Vol. 172, pages 1055-1063 (October, 1990), also attempted to produce a chimeric mouse capable of both murine and human cell mediated immune response and humoral immune response by implanting human fetal thymus and fetal liver into immunodeficient SCID mice. However, the resulting Namikawa et al. mouse did not have a reconstituted murine immune system. Specifically, there were no murine T cells found in the mouse, indicating that murine T cell function was not restored. In addition, the Namikawa et al. chimeric mouse produced only transient human T cells. Finally, there was no primary human immune response in the Namikawa et al. mouse, nor was there any significant human or murine immune response.
Similarly, Mosier et al., in "Transfer of a Functional Human Immune System to Mice with Severe Combined Immunodeficiency", in Nature, Vol. 335, pages 256-259 (September, 1988), attempted to produce a chimeric mouse with a reconstituted murine immune system capable of mounting human antibody response to vaccinations with antigens such as tetanus toxoid. These mice were produced by injecting human peripheral blood leukocytes (PBL) into immunodeficient SCID mice to produce SCID-PBL mice. The chimeric mouse produced by Mosier et al. did show a low level of human immune response to the antigen tetanus toxoid. This probably reflected a secondary response to tetanus by the human PBL obtained from a donor already immunized with tetanus. However, the amount of human T cells in said mice decreased over a short period of time, and there was no human T cell maturation in such mice. In addition, the murine immune system was not reconstituted. As a result, the chimeric mouse produced by Mosier et al. was not capable of any significant murine and human primary immune response.
Finally, Taguchi et al., in "Development of Multiple Organ-Localized Autoimmune Diseases in Nude Mice After Reconstitution of T Cell Function by Rat Fetal Thymus Graft", in J. Exp. Med., Vol. 164, pages 60-71 (July, 1986), attempted to restore the murine immune system by implanting rat thymus into congenitally athymic nude mice. The chimeric mouse produced by Taguchi et al. produced very few rat lymphoid cells. In addition, murine T cell function was only somewhat restored. Further, in response to the implantation of rat thymus, the chimeric mouse developed autoantibodies and autoimmune diseases over a period of time.
Hence, a need exists for an animal which has a reconstituted animal immune system, contains target tissue susceptible to infection with human-specific pathogens, and is capable of mounting an immune response to human pathogens. Such an animal will allow researchers to determine whether a vaccine will cause an animal immune response which serves to protect human tissue in said animal.
Therefore, it is an object of this invention to produce an animal which is chimeric, and capable of both human and animal immune response, including cell mediated immune response and humoral immune response, said animal also containing target tissue for infection with human-specific pathogens.
It is another object of this invention to provide an animal system capable of responding to antigens by producing both human and murine T cells.
It is a further object of this invention to provide an animal system capable of responding to human-specific antigens by producing antigen-specific antibodies.
It is another object of this invention to provide a method of producing an animal system capable of both animal and human cellular and humoral immune response.
It is still another object of this invention to provide an animal system capable of responding to vaccines by the production of human and animal T cells and animal antibodies.
It is yet another object of this invention to provide a chimeric animal system for use in the production of both monoclonal and polyclonal antibodies.
It is a further object of this invention to provide an animal system useful for the study of human autoimmune diseases, human-specific pathogens and tissue-specific pathology.